Microbiologically active quaternary ammonium compounds



Unite 3,366,672 MICROBIOLOGICALLY ACTIVE QUATERNARY AMMONIUM COMPOUNDS Reginald L. Wakeman, Ph ladelphia, Pa, and Joseph F.

Coates, Washington, lD.C., assignors, by mesne assignments, to Millmaster Onyx Corporation, New York, N.Y.. a corporation of New York No Drawing. Filed Apr. 3, 1964, Ser. No. 357,304 6 Claims. (Cl. 26t)501.15)

The present invention has for its object the preparation of relatively water-insoluble, microbiologically active com pounds by reaction of certain quaternary amm nium hydroxides or their water-soluble salts with halogen-containing aromatic carboxylic acids or their water-soluble salts.

The quaternary ammonium compounds used in the process of this invention are all bacteriologically active, having a phenol coeflicient of at least 100 with respect to both Staphylococcus aureus and Salmonella typhosa at C., when determined by the standard method given in the United States Department of Agriculture Circular No. 198. They contain at least one carbon chain having from 8 to 22 carbon atoms and also possess at least one benzyl radical attached to the quaternary nitrogen atom. The benzyl radical may, if desired, be substituted by alkyl groups or halogen atoms. The quaternary ammonium compounds, moreover, possess only non-heterocyclic nitrogen atoms. In general, the quaternary ammonium compounds used in the present invention comply with the formula:

where R is an alkyl radical containing from 8 to 22 carbon atoms, an alkyl benzyl radical in which the benzyl group may contain a substituent methyl radical and in which the alkyl group contains 8 to 22 carbon atoms, or an alkyl phenoxy ethoxy ethyl radical in which the phenyl group may contain a substituent methyl radical and R" is a benzyl or substituted benzyl radical, or a methyl group if R is an alkyl benzyl radical containing eight or more carbon atoms in its alkyl substitutent. X in the above formula is chlorine, bromine, iodine, sulfate, .tnethosul= fate, ethosulfate and the like.

Typical examples of these quaternary ammonium compounds are alkyl dimethyl benzyl ammonium chloride in which the alkyl group may have from 8 to 22 carbon atoms, alkyl dimethyl substituted benzyl ammonium chlo rides, in which the alkyl radical contains from 8 to 22 carbon atoms and in which the benzyl radical is substituted with one or more side chains containing from 1 to 4 carbon atoms such, for example, as methyl, dimethyl, trimethyl, tetramcthyl, ethyl, diethyl, isopropyl and tertiary butyl or with one, two, or more, halogen atoms such as chlorine and bromine, alkyl dimethyl menaphthyl ammonium chloride and alkyl dimethyl tetrahydromenaphthyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms, alkyl benzyl trimethyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms and in which the aromatic nucleus of the benzyl radical may, if desired, be substituted by one or more methyl or other lower alkyl groups, alkyl phenoxy ethoxy ethyl dimethyl benzyl ammonium chloride in which the alkyl radical may be isooctyl or nonyl, and mixtures of the aforesaid quaternary ammonium compounds,

The aromatic halogenated monocarboxylic acids which are used in the present invention correspond to the general formula, RCO H, where R is a halogen substituted bengene or naphthalene nucleus, or the halogen substituted tans 3,366,672 Patented Jan. 30, 1968 nucleus of diphenyl or diphenyl oxide. R may contain one or more fiuoro, chloro, bromo, or iodo radicals.

Typical examples of the halogenated aromatic carboxylic acids which may be used in the practice of this invention include o-, mand p-monofluorobenzoic and monochlorbenzoic acids, 2,4-dichlorbenzoic acid, 3,4-dichlorbenzoic acid, trichlorobenzoic acids, the mono-, di-, tri-, tetra-, and penta-bromobenzoic acids, 0-, m-, and p-iodobenzoic acid, the mono-, di-, and polychloronaphthoic acids, and the like.

The compounds of this invention may be prepared by mixing an aqueous solution of the quaternary ammonium salt or hydroxide of the kind defined above with an aqueous solution of the acid in question or with any of its water-soluble salts.

After thorough mixing, the organic product layer is separated from the aqueous layer (as with a separatory funnel) since two distinct phases are formed. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or unreacted materials. The solvent, if any, may be evaporated and the product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in which the starting materials are soluble will be satisfactory. Non-aqueous solvents facilitate the separation of by-product inorganic salt and reduce the need for vacuum drying to get an anhydrous product. When a non-aqueous medium is employed, it is usually necessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrapped water is irrelevant to the microbiological activity of the compounds. In other applications, re moval of water may be essential for reasons not related to biological activity.

An alternative method for the preparation of compounds especially applicable to the treatment of fabric, ropes, net, woven and non-woven fabric and reticulated or convoluted materials, involves a two-step process. In the first stei the material is passed through a bath containing the anionic moiety. Excess solution is removed by methods well known to those skilled in the art. The treated material is then passed through. a second bath wherein the concentration of quaternary ammonium cornpound is such that the material pickup will result in an equivalent amount of quaternary ammonium compound reacting with the anionic moiety, depositing the product in the most intimate way on the surface and in the interstices, convolutions and reticulations of the material.

The method of. adjustment of solution concentrat'on to achieve the required pickup is well known to those skilled in the art. The order of treatment may be reversed without affecting the biological activity or durability of the product on the material. The products of this invention may be formulated as water dispersions by dissolving them in a water-miscible organic solvent such as acetone or methanol and diluting with water or by dissolving them in em ulsifiable oils such, for example, as sulfonated castor oil or pine oil and diluting with water, In preparing aqueous dispersions, emulsifying agents such, for example, as ethylene oxide condensates of alkyl phenols may be used with or without organic solvents.

it is surprising that the compounds of this invention exhibit high microbiological activity despite their relative insolubility in water. Because of their unusual combination of physical and microbiological properties, they can be used to impart laundry-resistant anti-microbial characteristics to textiles. They can also be used as the active agent in antimildew finishes for textiles which are resistant to leaching with water.

Although the compounds have low water solubility, they are compatible with various organic solvents, plasticizers and high molecular weight compounds. Consequently, they may be incorporated as anti-microbial agents in synthetic resins and plastics. The compounds are compatible with natural and synthetic rubber latices. Therefore, they may be used to prepare bacteriostatic films and molded objects deposited from such latices.

The compounds can be incorporated into cutting and grinding fluids without precipitation. Also, they blend well with non-ionic and anionic surface active agents. in such compositions they retain their microbiological activity.

It will be understood that the properties of the products described herein will vary depending upon the nature of the quaternary ammonium compound used in their preparation as well as the aromatic carboxylic acid or salt reacted therewith.

The chemical, physical and biological properties of the products of our invention make them especialfy appropriate for the following applications when suftably incorporated in active amounts in an appropriate vehicle, binder, medium or substratei (l) Mildewiproofing fabric, canvas, ropes, 'textles, awnings, sails, tenting and other woven and non-woven reticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of microorganisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppresant for shoes and other leather products.

(6) Topical antiseptics.

(7) Antidandruff agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement, brick. and other inorganic building materials, to retard growth of microorganisms, fungi, mold and algae.

(1 l Wool preservative.

(12) Plant and tree spray to combat fungi.

(13) Antimycotic agents for soap wrappers.

(l4) Self-sanitizing brushes.

(15) Mildewproofing agent in and on plastic and film.

(l6) Mildewproofing of cellulosics, cardboard, fiberhoard, paper and cordage.

(17) Contact biostat for application to film, "waxes and cloth to preserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution, where low foaming is desirable.

(19) Paper pulp slime control.

(20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation. of metal-working compounds.

(25) Additives for soap and for both anionic and non-ionic detergents in liquid, bar, powder, bead, solution and other forms to impart bacteriostatic and fungistatic properties thereto.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard Tube Dilution Test, the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This test is used to determine the lowest concentration of microbiologically active compounds which will inhibit the growth of the organism in question. For a wide range of applications, the inhibition of growth rather than outright kill is satisfactory.

.Ilrictiy put, the Tube Dilution Test consists in placing A cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the microbiologically active compound at an appropriate conceutration is added to the test tube which is then inoculated with 0.1 cc. of a twenty-four hour old culture of the organism under study. The test tube is then incubated at 37 C. for forty-eight hours and observed for bacterial. growth.

The same procedure is followed for fungi. In such tests, however, the tubes are incubated for fourteen days at a temperature suitable for optimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the following examples:

Example I A stock solution was prepared containing 10 weight percent of the sodium salt of o-chlorobenzoic acid. To a vigorously agitated aliquot of this solution containing 0.035 equivalent weight of the compound was added the chemically equivalent amount of a 10 percent solution of a commercial grade of alkyl dimethyl ethyl benzyl ammonium chloride (Onyx Chemical Corporation, BTC- 471, in which the alkyl distribution is 50% C 30% C 17% C 3% C The agitated mixture was poured into a separatory funnel and separated into two phases. The organic product layer was removed and vacuum dried to yield a white paste in 100 percent theoretical yield of alkyl dimethyl ethyl-benzyl ammonium o-chlorobenzoate.

This product was found to be effective at a concentration of less than 25 parts per million in controlling sulfate-reducing bacteria present in oil floods. It is therefore useful in secondary oil recovery operations.

Similar products were prepared by replacing the hen zoic acid of this example with an equivalent amount of m-chlorobenzoic acid, p-chlorobenzoic acid, o-bromobem zoic acid, p-iodobenzoic acid, and p-fiuorobenzoic acid.

Example II A stock solution was prepared containing 10 weight percent of the sodium salt of 2,4-dichlorbenzoic acid. To a vigorously agitated aliquot of this solution containing 0.028 equivalent weight of the compound was added the chemically equivalent amount of a 10 percent solution of the alkyl dimethyl ethyl benzyl ammonium chloride of Example I. The agitated mixture was poured into a separatory funnel. The mixture separated into two phases. The organic product layer was removed and vacuum dried to yield a yellow syrup in percent theoretical yield of alkyl dimethyl ethyl-benzyl ammonium 2,4di-- chlorobenzoate.

When tested by the Standard Tube Dilution Test de scribed above, this product gave the following values for static dilution:

Staphylococcus aureus a-... ..MM. 1/10 Salmonella zyplzosa 1/10 Aspergillus niger H 1/10 A similar product, obtained as a yellow solid, was made by replacing the quaternary ammonium compound of this example with an equivalent amount of lauryl. dimethyl menaphthyl ammonium chloride.

Example 111 An aliquot of the stock solution in Example 11 con taining 0.028 equivalent of sodium 2,4-dichlorbenzoate was vigorously agitated while a chemically equivalent amount of alkyl dimethyl benzyl ammonium chloride (Onyx Chemical Corporation, BTC-824, in which the alkyl chain distribution is 60% C 30% C 5% C 5% C in the form of a 10 percent solution was slowly added. The agitated mixture was then poured into a separatory funnel. The mixture separated into two phases. The organic product layer was removed and vacuum dried to yield a yellow syrup in percent theoretical yield of alkyl dimethyl benZyl ammonium 2,4-dichloro benzoate.

When tested by the Standard Tube Dilution Test described above, this product gave the following values for static dilution:

Example IV A stock solution was prepared containing 10 weight percent of the sodium salt of 3,4-dichlorbenzoic acid. To a vigorously agitated aliquot of this solution containing 0.023 equivalent weights of the compound was added the chemically equivalent amount of a 10 ercent solution of the alkyl dimethyl ethyl benzyl ammonium chloride of Example I, The agitated mixture was poured into a separatory funnel. The mixture separated into two phases. The organic product layer was removed and vacuum dried to yield a white paste in 100 percent theoretical yield of alkyl dimethyl ethyl-benzyl ammonium 3,4- dichlorobenzoate.

When tested by the Standard Tube Dilution Test described above, this product gave the following values for. static dilution:

Staphylococcus aureus H 1/10 Salmonella typhosa n. 1/10 Aspergillus niger l/10 Certain products included within the scope of this in vention have been found effective in preventing the development of southern bean mosaic virus on Pinto beans. Thus, for example, when Pinto bean leaves inoculated with this vircus were sprayed fifteen minutes later with aqueous dispersions containing from 500 to 2000 parts per million of the product of Example II, there was a 97 to 100% reduction in lesions which. appeared on these leaves as contrasted with untreated controls. These compounds, moreover, exhibit relatively little or no phytotoxicity. At the lower concentration, i.e., 500 parts per million, they caused. neither suppression of growth nor plant injury.

We claim:

'1. A compound having the structure;

wherein R is a member of the group consisting of halogen-substituted benzene, halogen-substituted naphthalene, halogen-substituted diphenyl and the halogen-substituted diphenyl oxide, R is a member of the group consisting of alkyl containing 8 to 22 carbon atoms, alkyl benzyl wherein the alkyl contains 8 to 22 carbon atoms and alkyl methyl-substituted benzyl wherein the alkyl con tains 8 to 22 carbon atoms, and R" is a member of the group consisting of benzyl, lower alkyl-substituted benzyl, and methyl, R being methyl when R is alkyl benzyl.

2. Alkyl dimethyl ethyl-benzyl ammonium salt of a halogen-containing aromatic carboxylic acid selected from the group consisting of o-chloro-benzoic acid, mchlorobenzoic acid, p-chlorobenzoic acid, o-bromobenzoic acid and p-fluorobenzoic acid, wherein the alkyl group contains 8 to 22 carbon atoms.

3. Alkyl dimethyl ethyl-benzyl ammonium 2,4-dichl0 ro-benzoate, wherein the alkyl group contains 12 to 18 carbon atoms.

4. Alkyl dimethyl benzyl ammonium 2,4-dichlorobenzoate, wherein the alkyl group contains 12 to 18 carbon atoms.

5. Alkyl dimethyl ethyl-benzyl ammonium 3,4-dichlorobenzoate, wherein the alkyl group contains 12 to 18 carbon atoms.

6. Lauryl dimethyl menaphthyl ammonium 2,4-dichlorobenzoate, wherein the alkyl group contains 12 to .18 carbon atoms.

References Cited UNITED STATES PATENTS 2,108,765 2/1938 Dornagk 260567.6 2,676,986 4/1954 Wakeman et al. 260567.6 2,680,769 6/1954 Tesoro et al. M..-" 260-5676 OTHER REFERENCES Hager et al., J. Infectious Diseases, 71, 228-31 (1942), CA. relied on. Vol. 37, Column 2123 (1943).

Goldsworthy et al., U.S. Dept. of Agr. Plant Disease Repr. Supp. 182, 89-109 (1949), CA. relied on. Vol. 43, column 6351F (1949).

LORRAINE A. WEINBERGER, Primary Examiner. M. WEBSTER, Assistant Examiner. 

1. A COMPOUND HAVING THE STRUCTURE: 